This Article Full Text Full Text (PDF) All Versions of this Article: 90/3/1791    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Djouadi, F. Articles by Bastin, J. Search for Related Content PubMed PubMed Citation Articles by Djouadi, F. Articles by Bastin, J. Related Collections Metabolism

Peroxisome Proliferator Activated Receptor (PPAR) Agonist But Not PPAR Corrects Carnitine Palmitoyl Transferase 2 Deficiency in Human Muscle Cells

Institut National de la Santé et de la Recherche Médicale Unité 393, Hôpital Necker-Enfants Malades, 75015 Paris, France

Address all correspondence and requests for reprints to: Jean Bastin, Ph.D., Institut National de la Santé et de la Recherche Médicale Unité 393, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France. E-mail: bastin{at}necker.fr.

Type 2 carnitine palmitoyl transferase (CPT2) is involved in the transfer of long-chain fatty acid into the mitochondria. CPT2-deficient patients carry gene mutations associated with different clinical presentations, correlating with various levels of fatty acid oxidation (FAO) and residual CPT2 enzyme activity. We tested the hypothesis that pharmacological stimulation of peroxisome proliferator-activated receptors (PPAR) can stimulate FAO in CPT2-deficient muscle cells. Accordingly, we show that a 48-h treatment of CPT2-deficient myoblasts by bezafibrate restored FAO in patient cells. Specific agonists of PPAR (GW 0742), and, to a lower extent, PPAR (GW 7647) also stimulated FAO in control myoblasts. However, when tested in CPT2-deficient myoblasts, only the -agonist was able to restore FAO, whereas the -agonist had no effect. GW 0742 increased CPT2 mRNA levels, whereas no change in CPT2 transcripts was found in response to GW 7647. Bezafibrate and GW 0742 increased residual CPT2 activity and normalized long-chain acylcarnitine production by deficient cells. Finally, CPT1-B mRNA was also stimulated after PPAR agonist treatment, and this likely takes part in drug-induced increase of FAO in control muscle cells. In conclusion, this study clearly suggests that PPARs could be therapeutic targets for correction of inborn ß-oxidation defects in human muscle. Furthermore, these data also illustrate a selective control of ß-oxidation enzyme gene expression by PPAR, with no contribution of PPAR.

This article has been cited by other articles:

				J. Bastin, F. Aubey, A. Rotig, A. Munnich, and F. Djouadi Activation of Peroxisome Proliferator-Activated Receptor Pathway Stimulates the Mitochondrial Respiratory Chain and Can Correct Deficiencies in Patients' Cells Lacking Its Components J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1433 - 1441. [Abstract] [Full Text] [PDF]

				N. Stefan, C. Thamer, H. Staiger, F. Machicao, J. Machann, F. Schick, C. Venter, A. Niess, M. Laakso, A. Fritsche, et al. Genetic Variations in PPARD and PPARGC1A Determine Mitochondrial Function and Change in Aerobic Physical Fitness and Insulin Sensitivity during Lifestyle Intervention J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1827 - 1833. [Abstract] [Full Text] [PDF]

				F. Djouadi, F. Aubey, D. Schlemmer, J.P.N. Ruiter, R.J.A. Wanders, A.W. Strauss, and J. Bastin Bezafibrate increases very-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders Hum. Mol. Genet., September 15, 2005; 14(18): 2695 - 2703. [Abstract] [Full Text] [PDF]